There is little doubt that the gut plays a seminal role in the pathophysiology of the body's response to hemorrhagic shock and the subsequent development of ileus, the systemic inflammatory response syndrome (SIRS) and multiple organ dysfunction syndrome (MODS). We and others have contributed to understanding the molecular consequences of hemorrhagic shock to the body by primarily using a simple hemorrhage only model, commonly referred to as the Weigert model. Although mechanistically valuable, this model may not adequately represent the clinical situation, and, therefore, may seriously limit conclusions and therapeutic insight into the treatment of injured patients, which frequently present with traumatic-hemorrhagic shock (T-HS). Certainly a combined trauma-hemorrhagic shock model presents a more experimentally complicated paradigm, however, our preliminary data and the existing literature has led us to hypothesize that traumatic-hemorrhagic shock triggers a synergistic, definable inflammatory scenario of molecular and functional events that significantly contributes to the complex sequelae of this devastating clinical problem. This proposal is designed to mechanistically investigate and establish a logical thread of data connecting specific events, which are seminal to understanding the detrimental synergy of the combined injuries of trauma and hemorrhage. We propose that hemorrhagic shock rapidly activates the transcription factor early gene response-1 (Egr-1), which is know to play a key role in upregulating CD44 transcriptional activity. The greatly enhanced expression of CD44 (the glycoprotein membrane receptor for extracellular matrix (ECM) products) and the release of its ligands (fragmented hyaluronic acid) from traumatize tissue results in the synergistic triggering of an inflammatory cascade of events, which participates in causing the generation of copious amounts of gut-derived inflammatory mediators (IL-lbeta, IL-6, TNF-alpha, MCP-1, iNOS, COX-2, MMPs), mucosal barrier function breakdown (iNOS) and ileus (iNOS and COX-2) with the leakage of luminal toxic products. We hypothesize that these events are key to the development of intestinal inflammation, SIRS and MODS.